Role of Microglia in Complement-Mediated CNS Synapse Elimination during Development and Disease

Beth Stevens, Ph.D.

Children's Hospital Boston

Funded in June, 2010: $200000 for 3 years

Immune system processes affect neural communication in the developing and degenerating brain

Investigators will use cellular imaging in mice to study how innate immune system processes prune inactive brain synapses during development, and also how they eliminate synapses in neurodegenerative diseases in a mouse model of glaucoma.

During development, brain cell connections (synapses) undergo remodeling as inactive or excess synapses are pruned and remaining synapses are strengthened. Later in life, during neurodegenerative diseases such as Alzheimer’s disease and glaucoma, synapses are lost as brain cells die. While we traditionally think of synaptic activities as neural processes, innate immune cells called microglia play a potentially significant role. Microglia are the only immune cells that reside in the brain, The Boston researchers discovered that certain proteins (called C1q and C3) involved in immune system functions are found at synapses in both the developing and degenerating brain. They hypothesize that these proteins coat and tag certain synapses to be eaten (“phagocytosed”) by immune microglial cells.

Using a combination of Array Tomography, electron microscopy and two-photon time lapse imaging in mice, they will determine: 1) whether microglia actively eat developing synapses; and, 2) if so, whether these C1q and C3 proteins are integral to that process by coating and tagging the target synapses Additionally, since levels of these proteins are increased in glaucoma and other neurodegenerative diseases, they will 3) use these imaging and molecular techniques to see whether microglia promote early synapse loss in a mouse model of glaucoma.

Significance: Ultimately, the findings may help to understand normal synaptic loss, how this process may go awry in developmental disorders, and how reactivation of synaptic elimination in glaucoma might be targeted to prevent or treat this neurodegenerative disorder.